Abstract

The amyloid β (Aβ) peptide is thought to be a major culprit in Alzheimer disease (AD), and its production and degradation have been intensely investigated. Nevertheless, it remains largely unknown how Aβ pathology is modulated by the autophagy pathway. The study by Pickford and colleagues in this issue of the JCI shows that beclin 1, a multifunctional protein that also plays an important role in the autophagy pathway, affects some aspects of Aβ pathology in aged but not young transgenic mice expressing amyloid precursor protein (APP) (see the related article beginning on page 2190). These findings further support the notion that modulation of autophagy, in this case through beclin 1, may represent a novel therapeutic strategy for AD.

Authors

Figure 1

Steps in the autophagy pathway.

Autophagy is a process by which cytoplasmic contents are sequestered by autophagosomes and degraded upon fusion with lysosomes. Autophagy occurs at a basal level and is regulated by several pathways. Once autophagy is induced, an isolation membrane is formed by vesicle nucleation. Beclin 1 interacts with the Vps34 protein complex and is involved in this initial step by increasing the activity of Vps34 (a type of PI3K). Therefore, beclin 1 is a positive regulator of the autophagy pathway and promotes its induction. PE is conjugated to cytosolic LC3-I and converts it into lipidated LC3-II. LC3-II localizes to both the outside and the inside membranes of autophagosomes and therefore is often used as a marker. After their formation, autophagosomes mature through fusion with endosomal compartments and with lysosomes to form autolysosomes for degradation of cytosolic components. In the endosomal/lysosomal pathway, mono-ubiquitination serves as a signal for targeting transmembrane cargo in early endosomes to multivesicular bodies. Aβ can be generated in multivesicular bodies and autophagosomes. The study by Pickford et al. in this issue of the JCI (10) reports that increased levels of beclin 1 reduces levels of Aβ, presumably through enhanced autophagic activity, although the detailed mechanism remains unclear.